MAP0004, Orally Inhaled DHE

A Randomized, Controlled Study in the Acute Treatment of Migraine

Sheena K. Aurora, MD; Stephen D. Silberstein, MD; Shashidhar H. Kori, MD; Stewart J. Tepper, MD; ScottW. Borland, MS; Min Wang, PhD; DavidW. Dodick, MD

Disclosures

Headache. 2011;51(4):507-517. 

In This Article

Discussion

MAP0004 was effective in relieving all symptoms of migraine with a favorable AE profile in the present study. The 2-hour response rates were similar to or higher than those reported in recently published phase 3 trials of other migraine investigations, even though there were more migraineurs treated in this study that had severe pain at the time of treatment.[21–23] In total, 46.2% of migraineurs in this study reported severe migraine pain, in contrast to 36.6% and 40.6% in the reported sumatriptan-naproxen studies[21] and 37.5% and 35.5% in reported telcagepant trials.[22,23]

The speed of onset of any given drug is dependent, at least in part, on its rate of absorption.[24] In a prior study, MAP0004 provided statistically significant pain relief at 10 minutes, which is likely related to its rapid absorption through the lung. In the present study, although more patients taking MAP0004 achieved pain relief at 10 minutes compared with those taking placebo, a statistically significant difference between the 2 treatments was not evident until 30 minutes. This finding is similar to that found in clinical studies of several of the marketed triptans.[19] Interestingly, patients who had severe pain at time of treatment achieved statistically significant pain relief compared with placebo at 10 minutes. Further studies to systematically evaluate the onset of action of MAP0004 may be warranted, as this pivotal phase 3 study was not specifically designed to evaluate time of onset.

Dihydroergotamine is generally considered to provide prolonged pain relief, and statistically significantly lower recurrence rates were observed after subcutaneous (SC) DHE treatment in a head-to-head comparison vs SC sumatriptan.[25] Potential explanations include longer drug half-life, prolonged binding to target receptors, and earlier and more complete intervention in the migraine event cascade. The present data confirm the prolonged effect of DHE. Both SPR and SPF from 2–24 hours and 2–48 hours were significant for MAP0004 compared with placebo (all P < .0001), illustrating this effect. The SPF 2- to 24-hour therapeutic gain observed with MAP0004 was 16% and is similar to 2- to 24-hour SPF values observed in phase 3 trials of sumatriptan/naproxen and telcagepant.[21,22] SPR 2–48 and SPF 2–48 hour rates are rarely reported but were both statistically significant for MAP0004. Headache recurrence over 24 hours, defined as the return of headache to moderate or severe within 24 hours of dosing in subjects who had pain relief within 2 hours of dosing, was 6% for MAP0004 and 15% for placebo.

MAP0004 was well tolerated in this study. As anticipated, the rate of nausea was low. The low rate of AEs observed here is similar to that seen in previous studies[18,19,26] with MAP0004 and may be explained by the pharmacokinetic profile and the lower Cmax of orally inhaled DHE compared with IV DHE.[18] Triptan sensations including chest pain, chest discomfort, paresthesias, and flushing were rare. Lack of statistically significant changes in pulmonary function and laboratory measures support the safety of the inhaled route as an alternative to address limitations of oral, nasal, and injectable/IV therapies.

An open-label extension portion of this study examining long-term safety is ongoing, and additional studies are planned to further evaluate the efficacy, tolerability, and safety profile of MAP0004.

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